How does copper exposure perturb neuronal cells leading to cell death? This application seeks to address this question by studying novel mechanisms that we discovered whose genetic defects confer susceptibility to or protect against metal toxicants. We propose that these copper homeostasis mechanisms are shared with pathways affected in common neurodegenerative disorders, such as Parkinson?s disease.Copperisanessentialmicronutrientbut,inaddition,copperisalsoapowerful neurotoxicant whose free levels in the cytoplasm must be tightly controlled. Here we focusonageneticdefectthatrenderscellssusceptibletocopper,Menkesdisease,such thatnormalenvironmentalcopperbecomestoxictocellsinculture.Menkesdisease,isa progressive childhood neurodegeneration caused by mutations of the copper pump ATP7A. In this application, we present exciting data revealing novel mechanisms associated to Menkes copper toxicity which are shared with genetic forms of neurodegeneration.Wepostulatethatcoppertoxicityismodulatedbymembranetraffic mechanisms controlling copper transporters expression and subcellular location, ubiquitination, and mitochondrial metabolism. This proposal will test this hypothesis in mice and Drosophila carrying mutations in pathways associated to ATP7A. Genetic defects in these ATP7A regulatory pathways also cause neurodegeneration. The completion of this proposal will open the door for clinical interventions to improve outcomes of neurological diseases where environmental factors participate in pathogenesis.